1448189-45-4

Upstream product

• 1448191-54-5 tert‐butyl (2S,4R)‐4‐hydroxy‐2‐({[4‐(4‐methyl‐1,3‐thiazol‐5‐yl)phenyl]methyl}carbamoyl)pyrrolidine‐1‐carboxylate 
• 1448189-28-3 2-(trimethylsilyl)ethyl 4-bromobenzylcarbamate 
• 1448189-29-4 2-(trimethylsilyl)ethyl 4-(4-methylthiazol-5-yl)benzylcarbamate 
• 1448189-30-7 1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methaneamine 
• 623-00-7 4-bromobenzenecarbonitrile 
• 122957-57-7 4-(4-methyl-1,3-thiazol-5-yl)benzonitrile 
• 13726-69-7 (2S,4R)-4-hydroxy-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid 
• 3959-07-7 4-Bromobenzylamine 
• 68819-84-1 tert-butyl N-(4-bromobenzyl)carbamate 
• 26177-44-6 4-bromobenzylamine hydrochloride 
• 1448189-89-6 tert-butyl (2S,4R)-2-[(4-bromophenyl)methylcarbamoyl]-4-hydroxypyrrolidine-1-carboxylate 

Downstream Products

• 1418120-86-1 C₂₅H₂₇N₃O₄S 
• 1418120-88-3 C₂₃H₂₂BrN₃O₃S 
• 1418120-90-7 C₂₃H₂₁BrClN₃O₃S 
• 1418120-92-9 C₂₄H₂₂N₄O₃S 
• 1418120-94-1 (2S,4R)-4-hydroxy-1-(3-hydroxybenzoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide 
• 1418120-96-3 C₂₄H₂₆N₄O₃S 
• 1448187-01-6 (2S,4R)-1-((S)-2-((S)-2-acetamido-4-methylpentanamido)propanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide 
• 1448187-02-7 (2S,4R)-1-((S)-2-((S)-2-amino-4-methylpentanamido)propanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide 
• 1448189-49-8 C₃₀H₄₃N₅O₆S 
• 1448186-85-3 (2S,4R)-4-hydroxy-1-(3-hydroxy-2-methylbenzoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide 
• 1448189-47-6 tert-butyl N-[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-1-oxopropan-2-yl]carbamate 
• 1448187-61-8 (2S,4R)-1-(2-(cyanomethyl)benzoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide 
• 1448190-14-4 tert-butyl ((S)-1-((2R,4S)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-1-oxopropan-2-yl)(methyl)carbamate 
• 1448187-26-5 (2S,4R)-4-hydroxy-1-((S)-2-(3-methoxypropanamido)propanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide 

Relevant academic research and scientific papers

MICROMOLECULAR COMPOUND SPECIFICALLYDEGRADING TAU PROTEIN, AND APPLICATION THEREOF

The present disclosure discloses a micromolecular compound specifically degrading tau protein, and an application thereof. The chemical structure of the micromolecular compound specifically degrading tau protein is TBM-L-ULM or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or N-oxide thereof, TBM being a tau protein-binding moiety, L being a linking group, and ULM being a ubiquitin ligase-binding moiety, the tau protein-binding moiety and the ubiquitin ligase-binding moiety being connected by means of the linking group. The micromolecular compound specifically degrading tau protein may increase tau protein degradation in a cell, thereby decreasing tau protein content.

Design, Synthesis, and Evaluation of VHL-Based EZH2 Degraders to Enhance Therapeutic Activity against Lymphoma

Traditional EZH2 inhibitors are developed to suppress the enzymatic methylation activity, and they may have therapeutic limitations due to the nonenzymatic functions of EZH2 in cancer development. Here, we report proteolysis-target chimera (PROTAC)-based EZH2 degraders to target the whole EZH2 in lymphoma. Two series of EZH2 degraders were designed and synthesized to hijack E3 ligase systems containing either von Hippel-Lindau (VHL) or cereblon (CRBN), and some VHL-based compounds were able to mediate EZH2 degradation. Two best degraders, YM181 and YM281, induced robust cell viability inhibition in diffuse large B-cell lymphoma (DLBCL) and other subtypes of lymphomas, outperforming a clinically used EZH2 inhibitor EPZ6438 (tazemetostat) that was only effective against DLBCL. The EZH2 degraders displayed promising antitumor activities in lymphoma xenografts and patient-derived primary lymphoma cells. Our study demonstrates that EZH2 degraders have better therapeutic activity than EZH2 inhibitors, which may provide a potential anticancer strategy to treat lymphoma.

BIFUNCTIONAL COMPOUNDS

The invention provides a bifunctional compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein said Targeting Ligand, Linker and Degron are as described herein.

Discovery of novel anti-angiogenesis agents. Part 11: Development of PROTACs based on active molecules with potency of promoting vascular normalization

Our recent investigation is focused on the discovery of anti-angiogenesis agents. Vascular normalization induced by anti-angiogenic agent appears to be a promising strategy. We have developed novel angiogenesis inhibitors with potency of promoting vascular normalization. Herein, we reported the design, synthesis and preliminary evaluation of proteolysis-targeting chimera (PROTACs) based on the previously developed anti-angiogenesis agents. Two PROTACs exhibited potent VEGFR-2 inhibition and anti-proliferative activity against HUVECs. Moreover, they were capable of reducing protein levels of VEGFR-2 in EA.hy926 cells without significant cytotoxicity against HEK293 cells. The novel PROTACs could be used to normalize the abnormal vessels, resulting in efficient delivery of drugs.

Discovery of SK-575 as a Highly Potent and Efficacious Proteolysis-Targeting Chimera Degrader of PARP1 for Treating Cancers

The nuclear protein poly(ADP-ribose) polymerase-1 (PARP1) has a well-established role in the signaling and repair of DNA and is a validated therapeutic target for cancers and other human diseases. Here, we have designed, synthesized, and evaluated a series of small-molecule PARP1 degraders based on the proteolysis-targeting chimera (PROTAC) concept. Our efforts have led to the discovery of highly potent PARP1 degraders, as exemplified by compound 18 (SK-575). SK-575 potently inhibits the growth of cancer cells bearing BRCA1/2 mutations and induces potent and specific degradation of PARP1 in various human cancer cells even at low picomolar concentrations. SK-575 achieves durable tumor growth inhibition in mice when used as a single agent or in combination with cytotoxic agents, such as temozolomide and cisplatin. These data demonstrate that SK-575 is a highly potent and efficacious PARP1 degrader.

PROTAC-mediated crosstalk between E3 ligases

Small-molecule heterobifunctional degraders can effectively control protein levels and are useful research tools. We assembled proteolysis targeting chimeras (PROTACs) from a cereblon (CRBN) and a von-Hippel-Lindau (VHL) ligase ligand and demonstrated a PROTAC-induced heterodimerization of the two E3 ligases leading to unidirectional and efficient degradation of CRBN.

ESTROGEN-RELATED RECEPTOR ALPHA BASED PROTAC COMPOUNDS AND ASSOCIATED METHODS OF USE

The present invention relates to bifunctional compounds, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds according to the present invention. In particular, the present invention is directed to compounds, which contain on one end a VHL ligand which binds to the ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. The present invention exhibits a broad range of pharmacological activities associated with compounds according to the present invention, consistent with the degradation/inhibition of targeted polypeptides.

Compounds & Methods for the Enhanced Degradation of Targeted Proteins & Other Polypeptides by an E3 Ubiquitin Ligase

The present invention relates to bifunctional compounds, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins that are degraded and/or otherwise inhibited by bifunctional compounds of the present invention. In particular, the present invention is directed to compounds, which contain on one end a VHL ligand that binds to the ubiquitin ligase and on the other end a moiety that binds a target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. The present invention exhibits a broad range of pharmacological activities associated with compounds of the present invention, consistent with the degradation/inhibition of targeted polypeptides.

COMPOUNDS AND METHODS FOR THE INHIBITION OF VCB E3 UBIQUITIN LIGASE

The present invention relates to novel compounds which find utility as modulators, especially inhibitors of VCB E3 Ubiquitin Ligase and as bioactive agents for use as therapeutics for the stimulation of erythropoiesis in a patient or subject including inducement of EPO production in the patient or subject, for the treatment of chronic anemia and ischemia (limits brain injury during episodes of localized anemia, ischemia and/or stroke and damage to cardiovascular tissue during cardiovascular ischemia), as well as enhancing wound healing processes. Pharmaceutical compositions comprising effective amounts of compounds according to the present invention alone or in combination with an additional erythropoieses stimulating agent such as EPO under the tradename procrit or epogen or darbapoietin alfa under the tradename aranesp. Methods of stimulating erythropoiesis in a subject or patient, including increasing the number of red blood cells and/or hematocrit of the patient, treating anemia, including chronic anemia and anemia associated with chronic kidney disease, dialysis, and cancer chemotherapy, ischemia, stroke and damage to cardiovascular tissue during cardiovascular ischemia as well as enhancing wound healing processes and preventing/reducing scarring secondary to healing represent additional aspects of the present invention. Local enhancement of angiogenesis through induction of VEGF including wound healing and reduction of stent occlusion remain additional aspects of the present invention.

Small-molecule inhibitors of the interaction between the E3 ligase VHL and HIF1α

By design: Novel small-molecule inhibitors of the interaction between the von Hippel-Lindau ligase (VHL) and its molecular target HIF1α, a transcription factor involved in oxygen sensing, have been developed and studied. The most potent inhibitor binds with an IC50 value of 0.9-μM and is thus the first sub-micromolar inhibitor of the VHL-HIF1α interaction. Copyright